bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–09–11
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Effect of cellular aging on memory T-cell homeostasis.
  2. Metabolic regulation and function of T helper cells in neuroinflammation.
  3. Defining the 'exhausted' T cells that respond to PD1 checkpoint blockade.
  4. Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.
  5. The Critical Role of AMPKα1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1Weak Signal-Induced T Cell Memory: An Interplay between Yin (AMPKα1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation.
  6. Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle.
  7. Nutritional Niches of Cancer Therapy-Induced Senescent Cells.
  8. Aging exacerbates the brain inflammatory micro-environment contributing to α-synuclein pathology and functional deficits in a mouse model of DLB/PD.
  1. Front Immunol. 2022 ;13 947242
    Effect of cellular aging on memory T-cell homeostasis.
    Arpit C Swain, José A M Borghans, Rob J de Boer.
      The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this 'homeostatic' regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, 'global' competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional 'cognate' competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the 'gold-standard'. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for 'cognate' competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the 'gold-standard' level of TCR diversity in the memory T-cell pool.
    Keywords:  Memory attrition; T cell; cellular aging; competitive exclusion; homeostatic regulation; mathematical modelling
    DOI:  https://doi.org/10.3389/fimmu.2022.947242
  2. Semin Immunopathol. 2022 Sep 06.
    Metabolic regulation and function of T helper cells in neuroinflammation.
    Martina Spiljar, Vijay K Kuchroo.
      Neuroinflammatory conditions such as multiple sclerosis (MS) are initiated by pathogenic immune cells invading the central nervous system (CNS). Autoreactive CD4+ T helper cells are critical players that orchestrate the immune response both in MS and in other neuroinflammatory autoimmune diseases including animal models that have been developed for MS. T helper cells are classically categorized into different subsets, but heterogeneity exists within these subsets. Untangling the more complex regulation of these subsets will clarify their functional roles in neuroinflammation. Here, we will discuss how differentiation, immune checkpoint pathways, transcriptional regulation and metabolic factors determine the function of CD4+ T cell subsets in CNS autoimmunity. T cells rely on metabolic reprogramming for their activation and proliferation to meet bioenergetic demands. This includes changes in glycolysis, glutamine metabolism and polyamine metabolism. Importantly, these pathways were recently also implicated in the fine tuning of T cell fate decisions during neuroinflammation. A particular focus of this review will be on the Th17/Treg balance and intra-subset functional states that can either promote or dampen autoimmune responses in the CNS and thus affect disease outcome. An increased understanding of factors that could tip CD4+ T cell subsets and populations towards an anti-inflammatory phenotype will be critical to better understand neuroinflammatory diseases and pave the way for novel treatment paradigms.
    Keywords:  Experimental autoimmune encephalomyelitis; Immunometabolism; Multiple sclerosis; Neuroimmunology; Neuroinflammation; Th17 cells
    DOI:  https://doi.org/10.1007/s00281-022-00959-z
  3. Nat Rev Immunol. 2022 Sep 05.
    Defining the 'exhausted' T cells that respond to PD1 checkpoint blockade.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-022-00778-1
  4. Nat Commun. 2022 Sep 06. 13(1): 4981
    Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.
    Qiang Feng, Zhida Liu, Xuexin Yu, Tongyi Huang, Jiahui Chen, Jian Wang, Jonathan Wilhelm, Suxin Li, Jiwon Song, Wei Li, Zhichen Sun, Baran D Sumer, Bo Li, Yang-Xin Fu, Jinming Gao.
      Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.
    DOI:  https://doi.org/10.1038/s41467-022-32521-8
  5. Int J Mol Sci. 2022 Aug 23. pii: 9534. [Epub ahead of print]23(17):
    The Critical Role of AMPKα1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1Weak Signal-Induced T Cell Memory: An Interplay between Yin (AMPKα1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation.
    Anjuman Ara, Zhaojia Wu, Aizhang Xu, Khawaja Ashfaque Ahmed, Scot C Leary, Md Fahmid Islam, Rajni Chibbar, Yue Wu, Jim Xiang.
      Two common γ-chain family cytokines IL-2 and IL-15 stimulate the same mammalian target of rapamycin complex-1 (mTORC1) signaling yet induce effector T (TE) and memory T (TM) cell differentiation via a poorly understood mechanism(s). Here, we prepared in vitro IL-2-stimulated TE (IL-2/TE) and IL-15-stimulated TM (IL-15/TM) cells for characterization by flow cytometry, Western blotting, confocal microscopy and Seahorse-assay analyses. We demonstrate that IL-2 and IL-15 stimulate strong and weak mTORC1 signals, respectively, which lead to the formation of CD62 ligand (CD62L)- killer cell lectin-like receptor subfamily G member-1 (KLRG)+ IL-2/TE and CD62L+KLRG- IL-15/TM cells with short- and long-term survival following their adoptive transfer into mice. The IL-15/mTORC1Weak signal activates the forkhead box-O-1 (FOXO1), T cell factor-1 (TCF1) and Eomes transcriptional network and the metabolic adenosine monophosphate-activated protein kinase-α-1 (AMPKα1), Unc-51-like autophagy-activating kinase-1 (ULK1) and autophagy-related gene-7 (ATG7) axis, increasing the expression of mitochondrial regulators aquaporin-9 (AQP9), mitochondrial transcription factor-A (TFAM), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), carnitine palmitoyl transferase-1 (CPT1α), microtubule-associated protein light chain-3 II (LC3II), Complex I and ortic atrophy-1 (OPA1), leading to promoting mitochondrial biogenesis and fatty-acid oxidation (FAO). Interestingly, AMPKα1 deficiency abrogates these downstream responses to IL-15/mTORC1Weak signaling, leading to the upregulation of mTORC1 and hypoxia-inducible factor-1α (HIF-1α), a metabolic switch from FAO to glycolysis and reduced cell survival. Taken together, our data demonstrate that IL-15/mTORC1Weak signaling controls T-cell memory via activation of the transcriptional FOXO1-TCF1-Eomes and metabolic AMPKα1-ULK1-ATG7 pathways, a finding that may greatly impact the development of efficient vaccines and immunotherapies for the treatment of cancer and infectious diseases.
    Keywords:  AMPKα1; FOXO1; IL-15; T-cell memory; autophagy; fatty acid oxidation; mTORC1; mitochondrial biogenesis
    DOI:  https://doi.org/10.3390/ijms23179534
  6. Aging (Albany NY). 2022 Sep 08. 14(undefined):
    Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle.
    Lei Liu, Xianlin Yue, Zewei Sun, William S Hambright, Qi Feng, Yan Cui, Johnny Huard, Paul D Robbins, Zhihui Wang, Xiaodong Mu.
      The aging of the immune system, or immunosenescence, was recently verified to have a causal role in driving the aging of solid organs, while the senolytic elimination of senescent immune cells was found to effectively delay systemic aging. Our recent study also showed that immune cells in severely dystrophic muscles develop senescence-like phenotypes, including the increased expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Here we further investigated whether the specific clearance of senescent immune cells in dystrophic muscle may effectively improve the function of muscle stem cells and the phenotypes of dystrophic muscle. We observed increased percentage of senescent cells in macrophages from mdx/utro(-/-) mice (a murine model for muscular dystrophy disease, dystrophin-/-; utrophin-/-), while the treatment of mdx/utro(-/-) macrophages with senolytic drug fisetin resulted in reduced number of senescent cells. We administrated fisetin to mdx/utro(-/-) mice for 4 weeks, and observed obviously reduced number of senescent immune cells, restored number of muscle cells, and improve muscle phenotypes. In conclusion, our results reveal that senescent immune cells, such as macrophages, are greatly involved in the development of muscle dystrophy by impacting the function of muscle stem cells, and the senolytic ablation of these senescent cells with fisetin can be an effective therapeutic strategy for improving function of muscle stem cells and phenotypes of dystrophic muscles.
    Keywords:  cellular senescence; immunosenescence; muscular dystrophy; senolytics; stem cells
    DOI:  https://doi.org/10.18632/aging.204275
  7. Nutrients. 2022 Sep 02. pii: 3636. [Epub ahead of print]14(17):
    Nutritional Niches of Cancer Therapy-Induced Senescent Cells.
    Àngela Llop-Hernández, Sara Verdura, Elisabet Cuyàs, Javier A Menendez.
      Therapy-induced senescence (TIS) is a state of stable proliferative arrest of both normal and neoplastic cells that is triggered by exposure to anticancer treatments. TIS cells acquire a senescence-associated secretory phenotype (SASP), which is pro-inflammatory and actively promotes tumor relapse and adverse side-effects in patients. Here, we hypothesized that TIS cells adapt their scavenging and catabolic ability to overcome the nutritional constraints in their microenvironmental niches. We used a panel of mechanistically-diverse TIS triggers (i.e., bleomycin, doxorubicin, alisertib, and palbociclib) and Biolog Phenotype MicroArrays to identify (among 190 different carbon and nitrogen sources) candidate metabolites that support the survival of TIS cells in limiting nutrient conditions. We provide evidence of distinguishable TIS-associated nutrient consumption profiles involving a core set of shared (e.g., glutamine) and unique (e.g., glucose-1-phosphate, inosine, and uridine) nutritional sources after diverse senescence-inducing interventions. We also observed a trend for an inverse correlation between the intensity of the pro-inflammatory SASP provoked by different TIS agents and diversity of compensatory nutritional niches utilizable by senescent cells. These findings support the detailed exploration of the nutritional niche as a new metabolic dimension to understand and target TIS in cancer.
    Keywords:  cancer; glutamine; metabolism; miR146a; nutrition; senescence
    DOI:  https://doi.org/10.3390/nu14173636
  8. Mol Neurodegener. 2022 09 05. 17(1): 60
    Aging exacerbates the brain inflammatory micro-environment contributing to α-synuclein pathology and functional deficits in a mouse model of DLB/PD.
    Michiyo Iba, Ross A McDevitt, Changyoun Kim, Roshni Roy, Dimitra Sarantopoulou, Ella Tommer, Byron Siegars, Michelle Sallin, Somin Kwon, Jyoti Misra Sen, Ranjan Sen, Eliezer Masliah.
       BACKGROUND: Although ɑ-synuclein (ɑ-syn) spreading in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) has been extensively investigated, the role of aging in the manifestation of disease remains unclear.
    METHODS: We explored the role of aging and inflammation in the pathogenesis of synucleinopathies in a mouse model of DLB/PD initiated by intrastriatal injection of ɑ-syn preformed fibrils (pff).
    RESULTS: We found that aged mice showed more extensive accumulation of ɑ-syn in selected brain regions and behavioral deficits that were associated with greater infiltration of T cells and microgliosis. Microglial inflammatory gene expression induced by ɑ-syn-pff injection in young mice had hallmarks of aged microglia, indicating that enhanced age-associated pathologies may result from inflammatory synergy between aging and the effects of ɑ-syn aggregation. Based on the transcriptomics analysis projected from Ingenuity Pathway Analysis, we found a network that included colony stimulating factor 2 (CSF2), LPS related genes, TNFɑ and poly rl:rC-RNA as common regulators.
    CONCLUSIONS: We propose that aging related inflammation (eg: CSF2) influences outcomes of pathological spreading of ɑ-syn and suggest that targeting neuro-immune responses might be important in developing treatments for DLB/PD.
    Keywords:  Aging; Dementia with Lewy bodies; Inflammation; Microglia; Neurodegeneration; Parkinson’s disease; Preformed fibrils; RNA-seq; T cell infiltration; ɑ-synuclein
    DOI:  https://doi.org/10.1186/s13024-022-00564-6
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